Treatment of pervasive developmental disorders with redox-active therapeutics

ABSTRACT

Methods of treating or suppressing pervasive developmental disorders (PDDs) including; autistic disorder, Asperger&#39;s syndrome, childhood disintegrative disorder (CDD), Rett&#39;s disorder, and PDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivity disorder (ADHD) comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds as disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/155,288, filed Jan. 14, 2014, which is a divisional of U.S. patentapplication Ser. No. 13/651,330, filed Oct. 12, 2012, now U.S. Pat. No.8,653,144, which is a divisional patent application of U.S. patentapplication Ser. No. 12/555,700, filed Sep. 8, 2009, now U.S. Pat. No.8,314,153, which claims priority benefit of U.S. Provisional PatentApplication No. 61/191,696 filed Sep. 10, 2008. The content of thoseapplications are hereby incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

The application discloses redox-active compositions and methods usefulfor treatment, prevention, or suppression of diseases, developmentaldelays and symptoms of pervasive developmental disorders includingautistic spectrum disorders and/or attention deficit/hyperactivitydisorder.

BACKGROUND OF THE INVENTION

Pervasive developmental disorder (PDD) is a category of neurologicaldisorders characterized by severe and pervasive impairment in severalareas of development, including social interaction and communicationsskills. The five disorders under PDD are autistic disorder (autism),Asperger's syndrome, childhood disintegrative disorder (CDD), Rett'sdisorder, and PDD-not otherwise specified (PDD-NOS). Specific diagnosticcriteria for each of these disorders can be found in the Diagnostic &Statistical Manual of Mental Disorders (DSM-IV-TR) as distributed by theAmerican Psychiatric Association (APA). Autistic spectrum disorder (ASD)is an umbrella term that is used to represent a broad heterogeneousdisorder by collectively grouping autistic disorder Asperger's syndromeand PDD-NOS.

Autism, the most common of the pervasive developmental disorders,affects an estimated 1 in approximately 150 births. Estimates of theprevalence of ASD are in the range of 6.5 to 6.6 per 1000 based onAutism and Developmental Disabilities Monitoring Network Surveillance(Year 2002). Indeed, as of 2003-2004, as many as 1.5 million Americansare believed to have some form of autism. Autism is a childhoodencephalopathy characterized by deficiencies in social interaction andcommunication and by repetitive and stereotyped behaviors. Based onstatistics from the U.S. Department of Education and other governmentalagencies, autism is growing at a rate of 10-17 percent per year. Atthese rates, the Autism Society of America (ASA) estimates that theprevalence of autism could easily reach 4 million Americans in the nextdecade.

Of the other four PDD forms, Asperger's syndrome is closest to autism insigns and likely causes; Rett's disorder and childhood disintegrativedisorder share several signs with autism, but may have unrelated causes;PDD-not otherwise specified (PDD-NOS) is diagnosed when the criteria arenot met for a more specific disorder (Lord C, et al. “Autism spectrumdisorders” Neuron (2000) 28 (2): 355-63).

Autism is a complex serious developmental disability that interfereswith, among other things, the normal development of the brain in theareas of social interaction and communication skills, and which causesseverely restricted interests and repetitive behavior. Typically,autistic children and adults have difficulties in verbal and non-verbalcommunication, social interactions, and leisure or play activities.Autism can include language disorders with impaired understanding,echolalia, pronominal reversal (such as using you instead of “I” or “me”when referring to one's self), rituals and compulsive phenomena, anduneven intellectual development with mental retardation. Autisticchildren are also at increased risk of developing seizure disorders,especially during their teen years. Autism typically appears during thefirst three years of life and is the result of a neurological disorderthat affects the functioning of the brain.

The overall incidence of autism is, for the most part, globallyconsistent. Indeed, autism knows no racial, ethnic, or socialboundaries, and family income, lifestyle, and educational levels do notaffect the chance of autism's occurrence. However, it has been found tobe four times more prevalent in boys than girls. Oil the other hand,Rett's disorder is more prevalent in girls than boys.

Since being first described by Dr. Leo Kanner in 1943, the understandingof autism has grown tremendously. Although autism is defined by acertain set of behaviors, it is a spectrum disorder in that its symptomsand characteristics can be present in a wide variety of combinations,from mild to severe. Therefore, autistic children and adults can exhibitany combination of the behaviors in any degree of severity. Twoindividuals, both with the same diagnosis, may have varying skills anddisplay very different actions. Those only mildly affected may exhibitslight delays in language or communication and may face greaterchallenges in social interactions. For example, one may have difficultyinitiating and/or maintaining a conversation. Communication by autisticchildren or adults is often displayed as talking at others (for example,a monologue on a favorite subject that continues despite attempts byothers to interject comments).

Autism seems to cause those affected by it to process and respond toinformation in unique ways. In some individuals with PDD includingautism, aggressive and/or self-injurious behavior may exist. Thefollowing traits, as identified by the ASA, may also be present inpersons with autism: insistence on sameness or resistance to change;difficulty in expressing needs (i.e. uses gestures or pointing insteadof words); repeating words or phrases in place of normal, responsivelanguage; laughing, crying, or showing distress for reasons not apparentto others; preferring to be alone or an aloof manner; tantrums;difficulty in mixing with others; not wanting to cuddle or be cuddled;little or no eye contact; unresponsive to normal teaching methods;sustained odd play; spinning objects; inappropriate attachments toobjects; apparent over-sensitivity or under sensitivity to pain; no realfears of danger; marked physical over-activity or extremeunder-activity; uneven gross/fine motor skills; and/ornon-responsiveness to verbal cues (i.e. acts as if deaf although hearingtests in normal range).

Symptoms as in attention deficit hyperactivity disorder (ADHD) arefrequent among individuals with pervasive developmental disorders (PDD).Children meeting diagnostic criteria for a pervasive developmentaldisorder (PDD) display symptoms and impairment related to attentiondeficit hyperactivity disorder (ADHD) sufficient to warrant a diagnosisof ADHD (Goldstein S, et al “The Comorbidity of Pervasive DevelopmentalDisorder and Attention Deficit Hyperactivity Disorder: Results of aRetrospective Chart Review” Journal of Autism and DevelopmentalDisorders, (2004) 34 (3):329-339). Hattori J, et al “Are PervasiveDevelopmental Disorders and Attention Deficit/Hyperactivity DisorderDistinct Disorders?” studied the relationship between patients withattention deficit/hyperactivity disorder (ADHD) and those with pervasivedevelopmental disorders (PDD), using the High-Functioning AutismSpectrum Screening Questionnaire (ASSQ) and ADHD Rating Scale-IV. Thepatients with strictly diagnosed ADHD had many PDD-related symptoms, andthe patients with PDD had many ADHD-related symptoms. It therefore seemsdifficult to make a distinction between ADHD and PDD by using thepresent diagnostic criteria in the DSM-IV.

People with autism have social impairments that appear early inchildhood and continue through adulthood. Autistic infants show lessattention to social stimuli, smile and look at others less often, andrespond less to their own name. Autistic toddlers have more strikingsocial deviance; for example, they have less eye contact andanticipatory postures and are more likely to communicate by manipulatinganother person's hand (Volkmar F, et al “Autism in infancy and earlychildhood,” Annu Rev Psychol (2005) 56: 315-36.) Three- to five-year-oldautistic children are less likely to exhibit social understanding,approach others spontaneously, imitate and respond to emotions,communicate nonverbally, and take turns with others. However, they doform attachments to their primary caregivers. (Sigman M, et al. “Earlydetection of core deficits in autism” Ment Retard Dev Disabil Res Rev.(2004) 10 (4): 221-33). They display moderately less attachment securitythan usual, although this feature disappears in children with highermental development or less severe autism spectrum disorders. Olderchildren and adults with ASD perform worse on tests of face and emotionrecognition (Sigman M. et al, see supra). Contrary to common belief,autistic children do not prefer to be alone. Making and maintainingfriendships often proves to be difficult for those with autism. Forthem, the quality of friendships, not the number of friends, predictshow lonely they are.

Unlike those with autism, people with Asperger's syndrome are notusually withdrawn around others; they approach others, even ifawkwardly, for example by engaging in a one-sided, long-winded speechabout a favorite topic while being oblivious to the listener's feelingsor reactions, such as signs of boredom or haste to leave.

About a third to a half of individuals with autism does not developenough natural speech to meet their daily communication needs; (Noens I,et al, “The ComFor: an instrument for the indication of augmentativecommunication in people with autism and intellectual disability”. JIntellect Disabil Res (2006) 50 (9): 621-32.) Differences incommunication may be present from the first year of life, and mayinclude delayed onset of babbling, unusual gestures, diminishedresponsiveness, and the desynchronization of vocal patterns with thecaregiver. In the second and third years, autistic children have lessfrequent and less diverse babbling, consonants, words, and wordcombinations; their gestures are less often integrated with words.Autistic children are less likely to make requests or share experiences,and are more likely to simply repeat others' words or reverse pronouns.

For individuals with autism, sensory integration problems are common. Inparticular, their senses may be either over or under-active. The fuzz ofa kiwi may actually be experienced as painful; a sweet, fruity smell maycause a gagging reflex. Some children or adults with autism areparticularly sensitive to sound, so that even the most ordinary dailynoises are painful.

Although there is no single known cause for autism, it is generallyaccepted that it is caused by abnormalities in brain structure orfunction. The shape and structure of the brain in autistic versusnon-autistic children show differences when brain scans are viewed.Currently the links between heredity, genetics and medical problems arebeing investigated by researchers, as well as a number of othertheories. The theory of a genetic basis of the disorder is supported bythe fact that, in many families, there appears to be a pattern of autismor related disabilities. While no one gene has been identified ascausing autism, researchers are searching for irregular segments ofgenetic code that autistic children may have inherited. Whileresearchers have not yet identified a single trigger that causes autismto develop, it also appears that some children are born with asusceptibility to autism.

Other researchers are investigating the possibility that under certainconditions, a cluster of unstable genes may interfere with braindevelopment resulting in autism. Still other researchers areinvestigating problems during pregnancy or delivery as well asenvironmental factors such as viral infections, metabolic imbalances,and exposure to environmental chemicals. Yet other researchers areinvestigating the link between autism and chemical toxicity, inparticular with the mercury-containing vaccine preservative thimerosal.

Some cases of autism have been associated with several different organicconditions, including bioenergetic metabolism deficiency suggested bythe detection of high lactate levels in some patients (Coleman M. et al,Autism and Lactic Acidosis, J. Autism Dev Disord., (1985) 15: 1-8;Laszlo et al Serum serotonin, lactate and pyruvate levels in infantileautistic children, Clin. Chim. Acta (1994) 229:205-207; and Chugani etal., Evidence of altered energy metabolism in autistic children, Progr.Neuropsychopharmacol Biol Psychiat., (1999) 23:635-641) and by nuclearmagnetic resonance imagining as well as positron emission tomographyscanning which documented abnormalities in brain metabolism. Althoughthe mechanism of hyperlactacidemia remains unknown, a likely possibilityinvolves mitochondrial oxidative phosphorylation dysfunction in neuronalcells. A small subset of autistic patients diagnosed with deficienciesin complex I or III of the respiratory chain have been reported in theliterature (see Oliveira, G., Developmental Medicine & Child Neurology(2005) 47 185-189; and Filipek, P A et al., Journal of Autism andDevelopmental Disorders (2004) 34:615-623.) However, in many of thecases of autism where there is some evidence of mitochondrialdysfunction, there is an absence of the classic features associated withmitochondrial disease, such as mitochondrial pathology in muscle biopsy(see Rossignol, D. A. et al., Am J. Biochem. & Biotech, 4 (2) 208-217).

The main goals of treatment are to lessen associated deficits and familydistress, and to increase quality of life and functional independence.No single treatment is best and treatment is typically tailored to thechild's needs. Intensive, sustained special education programs andbehavior therapy early in life can help children acquire self-care,social, and job skills, (Myers S M, et al. “Management of children withautism spectrum disorders” Pediatrics (2007) 120 (5): 1162-82) andAngley M, et al. “Children and autism—part 1—recognition andpharmacological management” Aus.t Fam. Physician (2007) 36 (9): 741-4)and often improve functioning and decrease symptom severity andmaladaptive behaviors; (Rogers S J, et al., “Evidence-basedcomprehensive treatments for early autism” J Clin. Child Adolesc.Psychol. (2008) 37 (1): 8-38).

Medications have not been proven to correct deficits of ASDs and are notthe primary treatment. They are used to treat problems associated withautism disorders, such as associated maladaptive behaviors orpsychiatric comorbidities that may interfere with educational progress,socialization, health or safety and quality of life. More than half ofU.S. children diagnosed with autistic disorders are prescribedpsychoactive drugs or anticonvulsants, with the most common drug classesbeing antidepressants, stimulants, and antipsychotics. (Oswald D P, etal. “Medication Use Among Children with Autism Spectrum Disorders”. JChild Adolesc Psychopharmacol (2007) 17 (3): 348-55.) Aside fromantipsychotics, there is scant reliable research about the effectivenessor safety of drug treatments for children, adolescents or adults withASD. A person with ASD may respond atypically to medications, themedications can have adverse effects, and no known medication relievesautism's core symptoms of social and communication impairments.Alternative nutritional therapies for autistic children may includeIdebenone and CoQ10, because of their superior antioxidant properties,but no studies have been performed to prove their efficacy.

US Patent Publication 2005/0203066 discloses compounds, compositions andmethods for treatment of developmental delay in cognitive, motor,language, executive function or social skills with a pyrimidinenucleotide precursor, but it does not disclose any compounds,compositions or methods of treatment with compounds of the presentinvention.

Attention deficit hyperactivity disorder (ADHD)—also referred to asADD—is a biological, brain based condition that is characterized by poorattention and distractibility and/or hyperactive and impulsivebehaviors. It is one of the most common mental disorders that develop inchildren. Symptoms may continue into adolescence and adulthood. If leftuntreated, ADHD can lead to poor school/work performance, poor socialrelationships and a general feeling of low self esteem. The mostprevalent symptoms of ADHD are inattention and distractibility and/orhyperactive and impulsive behaviors. Difficulties with concentration,mental focus, and inhibition of impulses and behaviors are chronic andpervasive and impair an individual's daily functioning across varioussettings—home, school or work, in relationships, etc. ADD or attentiondeficit disorder is a general term frequently used to describeindividuals that have attention deficit hyperactivity disorder (ADHD)without the hyperactive and impulsive behaviors. The terms are oftenused interchangeably for both those who do and those who do not havesymptoms of hyperactivity and impulsiveness.

Thus, there is an unmet need for improved methods of treating patientswith pervasive developmental disorders, particularly with autism and/orattention deficit/hyperactivity disorder (ADHD).

SUMMARY OF THE INVENTION

The present invention provides methods and redox-active compositionsthat can reduce the symptoms of autism in a human patient. Briefly, themethods and compositions comprise administering a physiologicallyeffective amount of one or both of in sufficient quantities to reducethe effects of the autism. When administered to human patients sufferingfrom autism, without restriction on the normal diet of the patients, thecompositions and methods reduce or improve one or more symptoms ofautism, such as increased eye contact, better enunciation and use ofpronouns, less fatigue, singing a song for the first time with themelody and words together and the entire song understandable, playingwith age appropriate friends for the first time, fewer tantrums, bettersleep patterns, improved politeness and coordination, being more loving,acknowledging another individual's emotion, and increased voice and wordassociation. The redox-active compounds of the present invention aresuperior because they show protective effect not only on cells ofautistic patients that have a mitochondrial dysfunction but also oncells of patients that do not show any impairment of mitochondrialenergy metabolism.

In one aspect, the invention embraces a composition for reducing thesymptoms associated with, or for treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-Not Otherwise Specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment comprising one ormore compounds of Formula I, Formula II, Formula III, Formula IV,Formula V, Formula VI or mixtures thereof,

-   wherein,-   the bonds indicated with a dashed line can independently be single    or double;-   R¹, R², and R³ are independently selected from H, (C₁-C₆)alkyl,    (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, halogen and CN;-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In another embodiment,    the bonds indicated with a dashed line are all single bonds. In    another embodiment, the bonds indicated with a dashed line are all    double bonds.

In one embodiment, R¹, R², and R³ are independently selected from(C₁-C₄)alkyl, and in a particular example R¹, R², and R³ are methyl. Inanother embodiment, at least one of R¹, R², and R³ is not methyl. Inanother embodiment, R¹ and R² are independently selected from(C₁-C₄)alkoxy, and R³ is (C₁-C₄)alkyl. In another embodiment, R¹ and R²are methoxy, and R³ is methyl.

In one embodiment, the invention embraces a composition for reducing thesymptoms associated with, or for treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment comprising one ormore compounds of Formula Ia, Formula IIa, Formula IIIa, Formula IVa,Formula Va, Formula VIa, or mixtures thereof,

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In another embodiment,    the bonds indicated with a dashed line are all single bonds. In    another embodiment, the bonds indicated with a dashed line are all    double bonds.

In another aspect, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of one or morecompounds of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, or mixtures thereof,

-   wherein,-   the bonds indicated with a dashed line can independently be single    or double;-   R¹, R², and R³ are independently selected from H, (C₁-C₆)alkyl,    (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, halogen and CN;-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In another embodiment,    the bonds indicated with a dashed line are all single bonds. In    another embodiment, the bonds indicated with a dashed line are all    double bonds.

In one embodiment, R¹, R², and R³ are independently selected from(C₁-C₄)alkyl, and in a particular example R¹, R², and R³ are methyl. Inanother embodiment, at least one of and R³ is not methyl. In anotherembodiment, R¹ and R² are independently selected from (C₁-C₄)alkoxy, andR³ is (C₁-C₄)alkyl. In another embodiment, R¹ and R² are methoxy, and R³is methyl.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of one or morecompounds of Formula Ia, Formula IIa, Formula IIIa, Formula IVa, FormulaVa, Formula VIa, or mixtures thereof,

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In another embodiment,    the bonds indicated with a dashed line are all single bonds. In    another embodiment, the bonds indicated with a dashed line are all    double bonds.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of one or morecompounds of Formula Id, Formula IId or mixtures thereof,

-   wherein,-   the bonds indicated with a dashed line can independently be single    or double;-   R¹, R², and R³ are independently selected from H, (C₁-C₄)alkyl, and    (C₁-C₄)alkoxy;-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In another embodiment,    the bonds indicated with a dashed line are all single bonds. In    another embodiment, the bonds indicated with a dashed line are all    double bonds.

In one embodiment, R¹, R², and R³ are independently selected from(C₁-C₄)alkyl, and in a particular example R¹, R², and R³ are methyl. Inanother embodiment, at least one of R¹, R², and R³ is not methyl. Inanother embodiment, R¹ and R² are independently selected from(C₁-C₄)alkoxy, and R³ is (C₁-C₄)alkyl. In another embodiment, R¹ and R²are methoxy, and R³ is methyl.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of a compound ofFormula Ib:

-   which is named    2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In particular, the    stereoisomers    2-((3R,6E,10E)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10-dienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione    and    2-((3S,6E,10E)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10-dienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione    (abbreviated as Ib-R and Ib-S, respectively) are included in this    embodiment.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing autisticspectrum disorder (ASD) in a patient in need of such treatment byadministering a therapeutically or physiologically effective amount of acompound of Formula Ib:

-   and an salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as Ib-R and Ib-S.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing autism in apatient in need of such treatment by administering a therapeutically orphysiologically effective amount of a compound of Formula Ib:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as Ib-R and Ib-S.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing attentiondeficit/hyperactivity disorder (ADHD) in a patient in need of suchtreatment by administering a therapeutically or physiologicallyeffective amount of a compound of Formula Ib:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as Ib-R and Ib-S.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of a compound ofFormula Ic:

-   which is named    2-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In particular, the    stereoisomers    2-((3R,7R,11R)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    2-((3S,7R,11R)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    2-((3R,7S,1R)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    2-((3R,7R,11S)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    2-((3S,7S,11R)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    2-((3S,7R,11S)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    2-((3R,7S,11S)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    and    2-((3S,7S,11S)-3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    (referred to as Ic-RRR, Ic-SRR, Ic-RSR, Ic-RRS, Ic-SSR, Ic-SRS,    Ic-RSS, and Ic-SSS, respectively) are included in this embodiment.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing an autisticspectrum disorder (ASD) in a patient in need of such treatment byadministering a therapeutically or physiologically effective amount of acompound of Formula Ic:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as Ic-RRR, Ic-SRR,    Ic-RSR, Ic-RSS, Ic-SRR, Ic-SRS, Ic-RSS, and Ic-SSS.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing autism in apatient in need of such treatment by administering a therapeutically orphysiologically effective amount of a compound of Formula Ic:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as Ic-RRR, Ic-SRR,    Ic-RSR, Ic-RRS, Ic-SSR, Ic-SRS, Ic-RSS, and Ic-SSS.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing attentiondeficit/hyperactivity disorder (ADHD) a patient in need of suchtreatment by administering a therapeutically or physiologicallyeffective amount of a compound of Formula Ic:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as Ic-RRR, Ic-SRR,    Ic-RSR, Ic-RRS, Ic-SSR, Ic-SRS, Ic-RSS, and Ic-SSS.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of one or morecompounds of Formula IIId, Formula IVd or mixtures thereof,

-   wherein,-   the bonds indicated with a dashed line can independently be single    or double,-   R¹, R², and R³ are independently selected from H, (C₁-C₆)alkyl, and    (C₁-C₆)alkoxy;-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In another embodiment,    the bonds indicated with a dashed line are all single bonds. In    another embodiment, the bonds indicated with a dashed line are all    double bonds.

In one embodiment, R¹, R², and R³ are independently selected from(C₁-C₄)alkyl, and in a particular example R¹, R², and R³ are methyl. Inanother embodiment, at least one of R¹, R², and R³ is not methyl. Inanother embodiment, R¹ and R² are independently selected from(C₁-C₄)alkoxy, and R³ is (C₁-C₄)alkyl. In another embodiment, R¹ and R²are methoxy, and R³ is methyl.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of a compound ofFormula IIIb:

-   which is named    2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)cyclohexa-2,5-diene-1,4-dione;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing an autisticspectrum disorder (ASD) in a patient in need of such treatment byadministering a therapeutically or physiologically effective amount of acompound of Formula IIIb:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing autism in apatient in need of such treatment by administering a therapeutically orphysiologically effective amount of a compound of Formula IIIb:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing attentiondeficit/hyperactivity disorder (ADHD) in a patient in need of suchtreatment by administering a therapeutically or physiologicallyeffective amount of a compound of Formula IIIb:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of a compound ofFormula IIIc:

-   which is named    2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof. In particular, the    stereoisomers    2,3,5-trimethyl-6-((3R,7R,11R)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione;    2,3,5-trimethyl-6-((3S,7R,11R)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione;    2,3,5-trimethyl-6-((3R,7S,11R)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione;    2,3,5-trimethyl-6-((3R,7R,11S)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione;    2,3,5-trimethyl-6-((3S,7S,11R)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione;    2,3,5-trimethyl-6-((3S,7R,11S)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione;    2,3,5-trimethyl-6-((3R,7S,11S)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-dione-1,4-dione;    and    2,3,5-trimethyl-6-((3S,7S,11S)-3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione    (abbreviated as IIIc-RRR, IIIc-SRR, IIIc-RSR, IIIc-RRS, IIIc-SSR,    IIIc-SRS, IIIc-RSS, and IIIc-SSS, respectively) are included in this    embodiment.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing an autisticspectrum disorder (ASD) in a patient in need of such treatment byadministering a therapeutically or physiologically effective amount of acompound of Formula IIIc:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as IIIc-RRR,    IIIc-SRR, IIIc-RSR, IIIc-RRS, IIIc-SSR, IIIc-SRS, IIIc-RSS, and    IIIc-SSS.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing autism in apatient in need of such treatment by administering a therapeutically orphysiologically effective amount of a compound of Formula IIIc:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as IIIc-RRR,    IIIc-SRR, IIIc-RSR, IIIc-RRS, IIIc-SSR, IIIc-SRS, IIIc-RSS, and    IIIc-SSS.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing attentiondeficit/hyperactivity disorder (ADHD) in a patient in need of suchtreatment by administering a therapeutically or physiologicallyeffective amount of a compound of Formula IIIc:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof, such as IIIc-RRR,    IIIc-SRR, IIIc-RSR, IIIc-RRS, IIIc-SSR, IIIc-SRS, IIIc-RSS, and    IIIc-SSS.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of a compound ofFormula Va or Formula VIa or mixtures thereof:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of a compound ofFormula Va:

-   which is named 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another aspect, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing an autisticspectrum disorder (ASD) in a patient in need of such treatment byadministering a therapeutically or physiologically effective amount of acompound of Formula Va:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another aspect, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing autism in apatient in need of such treatment by administering a therapeutically orphysiologically effective amount of a compound of Formula Va:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another aspect, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing attentiondeficit/hyperactivity disorder (ADHD) in a patient in need of suchtreatment by administering a therapeutically or physiologicallyeffective amount of a compound of Formula Va:

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof.

In another embodiment the invention embraces a composition wherein thecompound is selected from2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ib); Ib-R; Ib-S;2-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ic); IIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR; IIIc-SRS;IIIc-RSS; IIIc-SSS;2,3,4-trimethyl-6-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)cyclohexa-2,5-diene-1,4-dione(III-b);2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dioneIIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR; IIIc-RSS; IIIc-SSS;and 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing pervasivedevelopmental disorder (PDD), including autistic disorder, Asperger'ssyndrome, childhood disintegrative disorder (CDD), Rett's disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD), in a patient in need of such treatment by administeringa therapeutically or physiologically effective amount of one or morecompounds selected from2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ib); Ib-R; Ib-S;2-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ic); IIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR; IIIc-SRS;IIIc-RSS; IIIc-SSS;2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)cyclohexa-2,5-diene-1,4-dione(III-b);2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione(IIIc); IIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR; IIIc-SRS;IIIc-RSS; IIIc-SSS; and2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing an autisticspectrum disorder (ASD) in a patient in need of such treatment byadministering a therapeutically or physiologically effective amount ofone or more compounds selected from2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ib); Ib-R;2-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ic); IIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR; IIIc-SRS;IIIc-RSS; IIIc-SSS; and2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)cyclohexa-2,5-diene-1,4-dione(III-b);2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione(IIIc); IIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR, IIIc-SRS;IIIc-RSS; IIIc-SSS; and2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing autism in apatient in need of such treatment by administering a therapeutically orphysiologically effective amount of one or more compounds selected from2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ib); Ib-R; Ib-S;2-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ic); Ic-RRR; Ic-SRR; Ic-RSR; Ic-RRS; Ic-SSR; Ic-SRS; Ic-RSS; Ic-SSS;2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)cyclohexa-2,5-diene-1,4-dione(III-b);2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione(IIIc); IIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR; IIIc-SRS;IIIc-RSS; IIIc-SSS; and2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione.

In another embodiment, the invention embraces a method of reducing thesymptoms associated with, or of treating or suppressing attentiondeficit/hyperactivity disorder (ADHD) in a patient in need of suchtreatment by administering a therapeutically or physiologicallyeffective amount of one or more compounds selected from2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ib); Ib-S;2-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ic); Ic-RRR; Ic-SRR; Ic-RSR; Ic-RRS; Ic-SSR; Ic-SRS; Ic-RSS; Ic-SSS;2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)cyclohexa-2,5-diene-1,4-dione(III-b);2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione(IIIc); Ic-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS, IIIc-SSR; IIIc-SRS;IIIc-RSS; IIIc-SSS; and2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione.

In another embodiment, the invention embraces the use of one or morecompounds of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, or mixtures thereof,

-   wherein,-   the bonds indicated with a dashed line can independently be single    or double;-   R¹, R², and R³ are independently selected from H, (C₁-C₆)alkyl,    (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, halogen and CN;-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof; for reducing the    symptoms associated with, or for treating or suppressing pervasive    developmental disorders (PDDs) in a patient in need of such    treatment. In another embodiment, the bonds indicated with a dashed    line are all single bonds. In another embodiment, the bonds    indicated with a dashed line are all double bonds.

In another embodiment, the invention embraces the use of one or morecompounds of Formula Ia, Formula IIa, Formula IIIa, Formula IVa, FormulaVa, Formula VIa, or mixtures thereof,

-   and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates and hydrates thereof; for reducing the    symptoms associated with, or for treating or suppressing pervasive    developmental disorders (PDDs) in a patient in need of such    treatment. In another embodiment, the bonds indicated with a dashed    line are all single bonds. In another embodiment, the bonds    indicated with a dashed line are all double bonds.

In another embodiment, the invention embraces the use of one or morecompounds selected from2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ib); Ib-R; Ib-S;2-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(Ic); Ic-RRR; Ic-SRR; Ic-RSR; Ic-RRS; Ic-SSR; Ic-SRS; Ic-RSS; Ic-SSS;2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl)cyclohexa-2,5-diene-1,4-dione2,3,5-trimethyl-6-(3,7,11,15-tetramethylhexadecyl)cyclohexa-2,5-diene-1,4-dione(IIIc); IIIc-RRR; IIIc-SRR; IIIc-RSR; IIIc-RRS; IIIc-SSR; IIIc-SRS;IIIc-RSS; IIIc-SSS; and2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione for reducing thesymptoms associated with, or for treating or suppressing pervasivedevelopmental disorders (PDDs) in a patient in need of such treatment.

In any of the foregoing embodiments, the pervasive developmentaldisorder (PDD) can be selected from autistic spectrum disorder (ASD).

In any of the foregoing embodiments, the disorder can be attentiondeficit/hyperactivity disorder (ADHD)

In any of the foregoing embodiments, the symptoms treated by thecompounds of the present invention are selected from the group ofsymptoms consisting of eye contact avoidance, failure to socialize,attention deficit, poor mood, hyperactivity, anxiety, stimming, poorcomprehension, inappropriate speech, abnormal sound sensitivity, poordigestion, disrupted sleep, and perseveration, and where the decreasedincidence is measured relative to the incidence in the untreatedindividual.

In one embodiment, the present invention provides pharmaceuticalcompositions able to reduce the symptoms of autism in a patient,comprising a physiologically effective amount of one or more compoundsof Formula I, Formula II, Formula III, Formula IV, Formula V, FormulaVI, Formula Ia, Formula IIa, Formula IIIa, Formula IVa, Formula Va,Formula VIa, Formula Ib, Formula Ib-R, Formula Ib-S, Formula Ic, FormulaIc-RRR, Formula Ic-SRR, Formula Ic-RSR, Formula Ic-RRS, Formula Ic-SSR,Formula Ic-SRS, Formula Ic-RSS, Formula Ic-SSS, Formula IIIb, FormulaIIIc, Formula IIIc-RRR, Formula IIIc-SRR, Formula IIIc-RSR, FormulaIIIc-RRS, Formula IIIc-SSR, Formula IIIc-SRS, Formula IIIc-RSS, FormulaIIIc-SSS, Formula Id, Formula IId, Formula IIId, or Formula IVd, and atleast one of the group consisting of a physiologically acceptablecarrier, adjuvant, excipient, buffer and diluent.

In still a further aspect, the present invention provides foods, medicalfoods, functional foods, food supplements, or dietary supplementscomprising compositions of one or more compounds of Formula I, FormulaIII, Formula III, Formula IV, Formula V, Formula VI, Formula Ia, FormulaIIa, Formula IIIa, Formula IVa, Formula Va, Formula VIa, Formula Ib,Formula Ib-R, Formula Ib-S, Formula Ic, Formula Ic-RRR, Formula Ic-SRR,Formula Ic-RSR, Formula Ic-RRS, Formula Ic-SSR, Formula Ic-SRS, FormulaIc-RSS, Formula Ic-SSS, Formula IIIb, Formula IIIc, Formula IIIc-RRR,Formula IIIc-SRR, Formula IIIc-RSR, Formula IIIc-RRS, Formula IIIc-SSR,Formula IIIc-SRS, Formula IIIc-RSS, Formula IIIc-SSS, Formula Id,Formula IId, Formula IIId, or Formula IVd, and at least one of the groupconsisting of a physiologically or nutritionally acceptable carrier,adjuvant, excipient, buffer and diluent. In one embodiment, theinvention comprises a method of administering a therapeuticallyeffective amount or physiologically effective amount of the foods,medical foods, functional foods, food supplements, or dietarysupplements to a patient in need thereof. In another embodiment, theinvention comprises a method of reducing the symptoms associated with,or for treating or suppressing pervasive developmental disorder (PDD),including autistic disorder, Asperger's syndrome, childhooddisintegrative disorder (CDD), Rett's disorder, and PDD-Not OtherwiseSpecified (PDD-NOS); or attention deficit/hyperactivity disorder (ADHD),by administering a therapeutically effective amount or physiologicallyeffective amount of the foods, medical foods, functional foods, foodsupplements, or dietary supplements to a patient in need thereof,especially for reducing the symptoms associated with, or for treating orsuppressing, autistic spectrum disorder (ASD); or for reducing thesymptoms associated with or for treating or suppressing, attentiondeficit/hyperactivity disorder (ADHD).

In yet another aspect, the invention also provides articles ofmanufacture and kits containing materials useful for treating orsuppressing autistic spectrum disorder. The invention also provides kitscomprising any one or more of the compounds of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula Ia, Formula IIa,Formula IIIa, Formula IVa, Formula Va, Formula VIa, Formula Ib, FormulaIb-R, Formula Ib-S, Formula Ic, Formula Ic-RRR, Formula Ic-SRR, FormulaIc-RSR, Formula Ic-RRS, Formula Ic-SSR, Formula Ic-SRS, Formula Ic-RSS,Formula Ic-SSS, Formula IIIb, Formula IIIc, Formula IIIc-RRR, FormulaIIIc-SRR, Formula IIIc-RSR, Formula IIIc-RRS, Formula IIIc-SSR, FormulaIIIc-SRS, Formula IIIc-RSS, Formula IIIc-SSS, Formula Id, Formula IId,Formula IIId, or Formula IVd. In some embodiments, the kit of theinvention comprises the container described above.

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with ASDdisorder, or to suppress an ASD disorder in an individual.

In one embodiment, the invention also embraces modulating one or moreautism biomarkers, normalizing one or more autism biomarkers, orenhancing one or more autism biomarkers, comprising administering to asubject a therapeutically effective amount or physiologically effectiveamount of one or more compounds or compositions as described herein. Theinvention also embraces compounds and compositions as described herein,which are useful for modulating one or more autism biomarkers,normalizing one or more autism biomarkers, or enhancing one or moreautism biomarkers.

The present invention comprises multiple aspects, features andembodiments; where such multiple aspects, features and embodiments canbe combined and permuted in any desired manner.

These and other aspects, features and embodiments of the presentinvention will become evident upon reference to the remainder of thisapplication, including the following detailed description. In addition,various references are set forth herein that describe in more detailcertain compositions, and/or methods; all such references areincorporated herein by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods and compositions able to reducethe symptoms of pervasive developmental disorder including autisticspectrum disorder or attention deficit/hyperactivity disorder (ADHD) ina patient, including a human patient. Briefly, the compositions andmethods comprise administering a compound of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula Ia, Formula IIa,Formula IIIa, Formula IVa, Formula Va, Formula VIa, Formula Ib, FormulaIb-R, Formula Ib-S, Formula Ic, Formula Ic-RRR, Formula Ic-SRR, FormulaIc-RSR, Formula Ic-RRS, Formula Ic-SSR, Formula Ic-SRS, Formula Ic-RSS,Formula Ic-SSS, Formula IIIb, Formula IIIc, Formula IIIc-RRR, FormulaIIIc-SRR, Formula IIIc-RSR, Formula IIIc-RRS, Formula IIIc-SSR, FormulaIIIc-SRS, Formula IIIc-RSS, Formula IIIc-SSS, Formula Id, Formula IId,Formula IIId, or Formula IVd to a human patient in sufficient quantitiesto reduce the effects of the autistic disease or of the attentiondeficit disorder. An initial trial wherein compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula Ia,Formula IIa, Formula IIIa, Formula IVa, Formula Va, Formula VIa, FormulaIb, Formula Ib-R, Formula Ib-S, Formula Ic, Formula Ic-RRR, FormulaIc-SRR, Formula Ic-RSR, Formula Ic-RRS, Formula Ic-SSR, Formula Ic-SRS,Formula Ic-RSS, Formula Ic-SSS, Formula IIIb, Formula IIIc, FormulaIIIc-RRR, Formula IIIc-SRR, Formula IIIc-RSR, Formula IIIc-RRS, FormulaIIIc-SSR, Formula IIIc-SRS, Formula IIIc-RSS, Formula IIIc-SSS, FormulaId, Formula IId, Formula IIId, or Formula IVd are administered to humanpatients, without restriction on the normal diet of the patients, wouldprovide a significant number of the patients with a significantreduction of one or more symptoms, such as increased eye contact, betterenunciation and use of pronouns, less fatigue, singing a song for thefirst time with the melody and words together and the entire songunderstandable, playing with age appropriate friends for the first time,fewer tantrums, better sleep patterns, improved politeness andcoordination, being more loving, acknowledging another individual'semotion, increased voice and word association.

By “subject,” “individual,” or “patient” is meant an individual, morepreferably a mammal, most preferably a human.

“Treating” a disease with the compounds and methods discussed herein isdefined as administering one or more of the compounds discussed herein,with or without additional therapeutic agents, in order to reduce oreliminate either the disease or one or more symptoms of the disease, orto retard the progression of the disease or of one or more symptoms ofthe disease, or to reduce the severity of the disease or of one or moresymptoms of the disease. “Suppression” of a disease with the compoundsand methods discussed herein is defined as administering one or more ofthe compounds discussed herein, with or without additional therapeuticagents, in order to suppress the clinical manifestation of the disease,or to suppress the manifestation of adverse symptoms of the disease. Thedistinction between treatment and suppression is that treatment occursafter adverse symptoms of the disease are manifest in a subject, whilesuppression occurs before adverse symptoms of the disease are manifestin a subject. Suppression may be partial, substantially total, or total.Because the autism disorders are inherited, genetic screening can beused to identify patients at risk of the disease. The compounds andmethods of the invention can then be administered to asymptomaticpatients at risk of developing the clinical symptoms of the disease, inorder to suppress the appearance of any adverse symptoms.

“Therapeutic use” of the compounds discussed herein is defined as usingone or more of the compounds discussed herein to treat or suppress adisease, as defined above. A “therapeutically effective amount” of acompound is an amount of the compound, which, when administered to asubject, is sufficient to reduce or eliminate either a disease or one ormore symptoms of a disease, or to retard the progression of a disease orof one or more symptoms of a disease, or to reduce the severity of adisease or of one or more symptoms of a disease, or to suppress theclinical manifestation of a disease, or to suppress the manifestation ofadverse symptoms of a disease. A therapeutically effective amount can begiven in one or more administrations.

A “physiologically effective amount” of an active substance indicates anadequate amount of the active substances to have a significant,externally observable effect on the patient. Thus, such aphysiologically effective amount affects one or more of thecharacteristics in the patient without the need for special equipment todetermine the effect. For example, a physiologically effective amount ofa compound of the present invention has a significant, externallyobservable effect on the behavior of the patient by reducing one or moreof the symptoms of autism or other pervasive developmental disorder.Accordingly, one can determine whether an adequate amount of the activesubstance has been administered by watching the patient and observingwhether changes have occurred in the patient due to the activesubstance.

While the compounds described herein can occur and can be used as theneutral (non-salt) compound, the description is intended to embrace allsalts of the compounds described herein, as well as methods of usingsuch salts of the compounds. In one embodiment, the salts of thecompounds comprise pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts are those salts which can be administered as drugs orpharmaceuticals to humans and/or animals and which, upon administration,retain at least some of the biological activity of the free compound(neutral compound or non-salt compound). The desired salt of a basiccompound may be prepared by methods known to those of skill in the artby treating the compound with an acid. Examples of inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, and phosphoric acid. Examples of organicacids include, but are not limited to, formic acid, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, andsalicylic acid. Salts of basic compounds with amino acids, such asaspartate salts and glutamate salts, can also be prepared. The desiredsalt of an acidic compound can be prepared by methods known to those ofskill in the art by treating the compound with a base. Examples ofinorganic salts of acid compounds include, but are not limited to,alkali metal and alkaline earth salts, such as sodium salts, potassiumsalts, magnesium salts, and calcium salts; ammonium salts; and aluminumsalts. Examples of organic salts of acid compounds include, but are notlimited to, procaine, dibenzylamine, N-ethylpiperidine,N,N-dibenzylethylenediamine, and triethylamine salts. Salts of acidiccompounds with amino acids, such as lysine salts, can also be prepared.

The invention also includes all stereoisomers of the compounds,including diastereomers and enantiomers. The invention also includesmixtures of stereoisomers in any ratio, including, but not limited to,racemic mixtures. Unless stereochemistry is explicitly indicated in astructure, the structure is intended to embrace all possiblestereoisomers of the compound depicted. If stereochemistry is explicitlyindicated for one portion or portions of a molecule, but not for anotherportion or portions of a molecule, the structure is intended to embraceall possible stereoisomers for the portion or portions wherestereochemistry is not explicitly indicated.

The compounds can be administered in prodrug form. Prodrugs arederivatives of the compounds, which are themselves relatively inactivebut which convert into the active compound when introduced into thesubject in which they are used by a chemical or biological process invivo, such as an enzymatic conversion. Suitable prodrug formulationsinclude, but are not limited to, peptide conjugates of the compounds ofthe invention and esters of compounds of the inventions. Furtherdiscussion of suitable prodrugs is provided in H. Bundgaard, Design ofProdrugs, New York: Elsevier, 1985; in R. Silverman, The OrganicChemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R.L. Juliano (ed.), Biological Approaches to the Controlled Delivery ofDrugs (Annals of the New York Academy of Sciences, v. 507), New York:New York Academy of Sciences, 1987; and in E. B. Roche (ed.), Design ofBiopharmaceutical Properties Through Prodrugs and Analogs (Symposiumsponsored by Medicinal Chemistry Section, APhA Academy of PharmaceuticalSciences, November 1976 national meeting, Orlando, Fla.), Washington:The Academy, 1977.

Metabolites of the compounds are also embraced by the invention.

“C₁-C₆ alkyl” is intended to embrace a saturated linear, branched,cyclic, or a combination thereof, hydrocarbon of 1 to 6 carbon atoms.Examples of “C₁-C₆ alkyl” are methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl,cyclopropyl-methyl, methyl-cyclopropyl, pentyl, cyclopentyl, hexyl, andcyclohexyl, where the point of attachment of the alkyl group to theremainder of the molecule can be at any chemically possible location onthe alkyl fragment. “C₁-C₄ alkyl” is intended to embrace a saturatedlinear, branched, cyclic, or a combination thereof, hydrocarbon of 1 to4 carbon atoms. Examples of “C₁-C₄ alkyl” are methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,cyclobutyl.

“Halogen” or “halo” designates fluoro, chloro, bromo, and iodo.

“C₁-C₆ haloalkyl” is intended to embrace any C₁-C₆ alkyl substituenthaving at least one halogen substituent; the halogen can be attached viaany valence on the C₁-C₆ alkyl group. Some examples of C₁-C₆haloalkylare —CF₃, —CCl₃, —CHF₂, —CHCl₂, —CHBr₂, —CH₂F, —CH₂Cl.

In a first aspect, the present invention provides redox-activecompositions that are able to reduce the symptoms of PervasiveDevelopmental Disorder (PDD), including of Autistic Disorder, Asperger'ssyndrome, Childhood Disintegrative Disorder (CDD), Rett's Disorder, andPDD-not otherwise specified (PDD-NOS) or attention deficit/hyperactivitydisorder (ADHD) in a human patient. For example, the compositions areable to reduce or improve one or more symptoms, such as increased eyecontact, better enunciation and use of pronouns, less fatigue, fewertantrums, better sleep patterns, improved politeness and coordination,and increased voice and word association. In other words, thecompositions are able to produce an adequate reduction of one or more ofthe observable characteristics of autism by an amount that is observableto a human observer, such as a parent, physician or caretaker, withoutthe use of special devices such as microscopes or chemical analyticaldevices. The compositions reduce such symptoms by providing aphysiologically effective amount of one or more compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula Ia,Formula IIa, Formula IIIa, Formula IVa, Formula Va, Formula VIa, FormulaIb, Formula Ib-R, Formula Ib-S, Formula Ic, Formula Ic-RRR, FormulaIc-SRR, Formula Ic-RSR, Formula Ic-RRS, Formula Ic-SSR, Formula Ic-SRS,Formula Ic-RSS, Formula Ic-SSS, Formula IIIb, Formula IIIc, FormulaIIIc-RRR, Formula IIIc-SRR, Formula IIIc-RSR, Formula IIIc-RRS, FormulaIIIc-SSR, Formula IIIc-SRS, Formula IIIc-RSS, Formula IIIc-SSS, FormulaId, Formula IId, Formula IIId, or Formula IVd, and at least one of thegroup consisting of a physiologically acceptable carrier, adjuvant,excipient, buffer and diluent, which terms are used in their ordinarysense to indicate substances that assist in the packaging, delivery,absorption, or the physiological effect of the compounds. Thephysiologically acceptable carriers, adjuvants, excipients, buffers anddiluents are preferably nontoxic to recipients at the dosages andconcentrations employed. Representative samples include water, isotonicsaline solutions that are preferably buffered at physiological pH (suchas phosphate-buffered saline or Tris-buffered saline), mannitol,dextrose, glycerol, and ethanol, as well as selected polypeptides orproteins such as human serum albumin, maltodextrin, L-lysine, lactaseand other carbohydratases, lipase and non-specific proteases such aspapain. The carrier, adjuvant, excipient, buffer, or diluent may becombined with the compositions disclosed herein to provide compositionseither as liquid solutions or, preferably, in solid form. For example,when the compositions are to be administered orally, the compositionsmay be produced in any of powder, tablet or capsule form.

Synthesis of Compounds

The compounds of the present invention can be readily synthesized by avariety of methods known in the art. The synthesis of alpha-tocopherolquinone is detailed in several references, for example in U.S. Pat. No.3,406,188 and U.S. Pat. No. 4,310,465. The synthesis of benzoquinonetype compounds of the present invention is disclosed in co-owned USPatent Application Publication Nos. 2006/0281809, 2007/0072943, and2007/0225261.

Clinical Assessment of Autism

Carnitine Deficiency:

As documented by Filipek, P A et al, in J. Autism Dev. Disord. (2004)34:615-23 serum carnitine levels on 100 children with autism wereinvestigated, concurrently with serum pyruvate, lactate, ammonia, andalanine levels. Values of free and total carnitine (p<0.001), andpyruvate (p=0.006) were significantly reduced while ammonia and alaninelevels were considerably elevated (p<0.001) in the autistic subjects.The relative carnitine deficiency in these patients, accompanied byslight elevations in lactate and significant elevations in alanine andammonia levels, would suggest that assessing pyruvate, lactate,carnitine and ammonia levels may be useful when measured during routineevaluation of ASD children.

Lactic Acid (Lactate) Levels:

Some cases of autism have been associated with abnormal levels of lacticacid, as pyruvate levels increase and pyruvate is converted to lactateto maintain capacity for glycolysis (see Coleman, M. et al. Journal ofAutism and Developmental Disorders (1985) 15, 1-8.) Lactate levels canbe measured by taking samples of appropriate bodily fluids such as wholeblood, plasma, or cerebrospinal fluid. Using magnetic resonance, lactatelevels can be measured in virtually any volume of the body desired, suchas the brain. Whole blood, plasma, and cerebrospinal fluid lactatelevels can be measured by commercially available equipment such as theYSI 2300 STAT Plus Glucose & Lactate Analyzer (YSI Life Sciences, Ohio).

Lipid Peroxidation:

Lipid peroxidation has been found to be elevated in autism indicatingthat oxidative stress is increased in this disease. Lipid peroxidationcan be measured by quantifying the levels of malonyldialdehyde (MDA), anend product of fatty acid oxidation. Several assays exist for MDA inplasma, urine, and other specimens. Such assays include specificreagents for UV detection by HPLC (Steghens, J. P., et al., Free RadicBiol Med (2001) 31:242 and Pilz, J. Chromatogr B Biomed Sci appl (2000)742:315 and capillary electrophoresis (Korizis, K. N. et al., BiomedChromatogr 15:287 (2001)). A variety of lipid peroxidation productsincluding MDA can be quantified using the thiobarbituric acid reaction(K Fukanaga et al., Biomed Chromatogr (1998) 12:300).

Lipid peroxidation can also be quantified by measurement of urinarylevels of isoprostane F(2α)-VI, a marker of lipid peroxidation;2,3-dinor-thromboxane B(2), which reflects platelet activation; and6-keto-prostaglandin F(1α), a marker of endothelium activation, by meansof gas chromatography-mass spectrometry in subjects with autism andhealthy control subjects. Methods of detecting oxidant stress-relatedproducts are likewise known in the art. For example, enzyme immunoassaykits are commercially available from Cayman Chemical for determinationof isoprostane F(2α)-VI (Cayman Chemical cat. no. 516301); for2,3-dinor-thromboxane B(2) (Cayman Chemical cat. no. 519051), and for6-keto-prostaglandin F(1α) (Cayman Chemical cat. no. 5152111).

Antioxidant Proteins:

Levels of major antioxidant proteins, namely transferrin (iron-bindingprotein) and ceruloplasmin (copper-binding protein) in the serum, aresignificantly reduced in autistic children as compared to theirdevelopmentally normal non-autistic siblings. A striking correlation wasobserved between reduced levels of these proteins and loss of previouslyacquired language skills in children with autism. These results indicatethat altered regulation of transferrin and ceruloplasmin in autisticchildren who lose acquired language skills can be used for diagnosis ofdisease during evaluation of patients.

In one embodiment, the invention also embraces modulating one or moreautism biomarkers, normalizing one or more autism biomarkers, orenhancing one or more autism biomarkers, comprising administering to asubject a therapeutically effective amount or physiologically effectiveamount of one or more compounds or compositions as described herein. Theinvention also embraces compounds and compositions as described herein,which are useful for modulating one or more autism biomarkers,normalizing one or more autism biomarkers, or enhancing one or moreautism biomarkers.

“Autism biomarkers” include free carnitine levels, total carnitinepyruvate levels, ammonia levels, alanine levels, lactate levels,malonyldialdehyde (MDA) levels, isoprostane F(2α)-VI levels,2,3-dinor-thromboxane B(2) levels, 6-keto-prostaglandin F(1α) levels,transferrin levels and ceruloplasmin levels. These biomarkers can bemeasured in whole blood, serum, plasma, urine, cerebrospinal fluid,cerebral ventricular fluid, or any other biological samples, bodilyfluids, or body compartments.

The compounds and compositions of the invention can be used in subjectsor patients to modulate one or more autism biomarkers. Modulation ofautism biomarkers can be done to normalize autism biomarkers in asubject, or to enhance autism biomarkers in a subject.

Normalization of one or more autism biomarkers is defined as eitherrestoring the level of one or more such autism biomarkers to normal ornear-normal levels in a subject whose levels of one or more autismbiomarkers show pathological differences from normal levels (i.e.,levels in a healthy subject), or to change the levels of one or moreautism biomarkers to alleviate pathological symptoms in a subject.Depending on the nature of the autism biomarker, such levels may showmeasured values either above or below values in non-autistic subjects.For example, carnitine levels are sometimes reduced in autistic subjectsin comparison to non-autistic subjects, and an increase in the carnitinelevel may be desirable. Ammonia levels are sometimes higher in autisticsubjects in comparison to non-autistic subjects, and a decrease inammonia levels may be desirable. Normalization of autism biomarkers caninvolve restoring the level of autism biomarkers of an autistic subjectto within about at least two standard deviations of the non-autisticvalue, more preferably to within about at least one standard deviationof the non-autistic value, to within about at least one-half standarddeviation of the non-autistic value, or to within about at leastone-quarter standard deviation of the non-autistic value.

When an increase in an autism biomarker level is desired to normalizethe one or more such autism biomarkers, the level of the autismbiomarker in an autistic subject can be increased to within about atleast two standard deviations of the value in a non-autistic subject,more preferably increased to within about at least one standarddeviation of the non-autistic value, increased to within about at leastone-half standard deviation of the non-autistic value, or increased towithin about at least one-quarter standard deviation of the non-autisticvalue, by administration of one or more compounds or compositionsaccording to the invention. Alternatively, the level of one or more ofthe autism biomarkers can be increased by about at least 10% above thesubject's level of the respective one or more autism biomarkers beforeadministration, by about at least 20% above the subject's level of therespective one or more autism biomarkers before administration, by aboutat least 30% above the subject's level of the respective one or moreautism biomarkers before administration, by about at least 40% above thesubject's level of the respective one or more autism biomarkers beforeadministration, by about at least 50% above the subject's level of therespective one or more autism biomarkers before administration, by aboutat least 75% above the subject's level of the respective one or moreautism biomarkers before administration, or by about at least 100% abovethe subject's level of the respective one or more autism biomarkersbefore administration.

When a decrease in a level of one or more autism biomarkers is desiredto normalize the one or more autism biomarkers, the level of the one ormore autism biomarkers in an autistic subject can be decreased to alevel within about at least two standard deviations of the value in anon-autistic subject, more preferably decreased to within about at leastone standard deviation of the value in a non-autistic subject, decreasedto within about at least one-half standard deviation of the value in anon-autistic subject, or decreased to within about at least one-quarterstandard deviation of the value in a non-autistic subject, byadministration of one or more compounds or compositions according to theinvention. Alternatively, the level of the one or more autism biomarkerscan be decreased by about at least 10% below the subject's level of therespective one or more autism biomarkers before administration, by aboutat least 20% below the subject's level of the respective one or moreautism biomarkers before administration, by about at least 30% below thesubject's level of the respective one or more autism hiomarkers beforeadministration, by about at least 40% below the subject's level of therespective one or more autism biomarkers before administration, by aboutat least 50% below the subject's level of the respective one or moreautism biomarkers before administration, by about at least 75% below thesubject's level of the respective one or more autism biomarkers beforeadministration, or by about at least 90% below the subject's level ofthe respective one or more autism biomarkers before administration.

Enhancement of the level of one or more autism biomarkers is defined aschanging the extant levels of one or more autism biomarkers in anautistic subject to a level which provides beneficial or desired effectsfor the subject. Additional enhancement, beyond normalization, may benecessary in the event that normalizing the level of one or more autismbiomarkers does not suffice to bring about an improvement in symptoms.

Accordingly, when an increase in a level of one or more autismbiomarkers is beneficial to an autistic subject, enhancement of the oneor more autism biomarkers can involve increasing the level of therespective autism biomarker or autism biomarkers in the autistic subjectto about at least one-quarter standard deviation above the value in anon-autistic subject, about at least one-half standard deviation abovethe value in a non-autistic subject, about at least one standarddeviation above the value in a non-autistic subject, or about at leasttwo standard deviations above the value in a non-autistic subject.Alternatively, the level of the one or more autism biomarkers can beincreased by about at least 10% above the subject's level of therespective one or more autism biomarkers before enhancement, by about atleast 20% above the subject's level of the respective one or more autismbiomarkers before enhancement, by about at least 30% above the subject'slevel of the respective one or more autism biomarkers beforeenhancement, by about at least 40% above the subject's level of therespective one or more autism biomarkers before enhancement, by about atleast 50% above the subject's level of the respective one or more autismbiomarkers before enhancement, by about at least 75% above the subject'slevel of the respective one or more autism biomarkers beforeenhancement, or by about at least 100% above the subject's level of therespective one or more autism biomarkers before enhancement.

When a decrease in a level of one or more autism biomarkers is desiredto enhance one or more autism biomarkers, the level of the one or moreautism biomarkers in an autistic subject can be decreased by an amountof about at least one-quarter standard deviation of the value in anon-autistic subject, decreased by about at least one-half standarddeviation of the value in a non-autistic subject, decreased by about atleast one standard deviation of the value in a non-autistic subject, ordecreased by about at least two standard deviations of the value in anon-autistic subject. Alternatively, the level of the one or more autismbiomarkers can be decreased by about at least 10% below the subject'slevel of the respective one or more autism biomarkers beforeenhancement, by about at least 20% below the subject's level of therespective one or more autism biomarkers before enhancement, by about atleast 30% below the subject's level of the respective one or more autismbiomarkers before enhancement, by about at least 40% below the subject'slevel of the respective one or more autism biomarkers beforeenhancement, by about at least 50% below the subject's level of therespective one or more autism biomarkers before enhancement, by about atleast 75% below the subject's level of the respective one or more autismbiomarkers before enhancement, or by about at least 90% below thesubject's level of the respective one or more autism biomarkers beforeenhancement.

Pharmaceutical, Nutraceutical and Nutritional Formulations

The compounds described herein can be formulated as pharmaceuticalcompositions by formulation with additives such as pharmaceuticallyacceptable excipients, pharmaceutically acceptable carriers, andpharmaceutically acceptable vehicles, or as nutraceutical or nutritionalformulations with additives such as nutraceutically or nutritionallyacceptable excipients, nutraceutically or nutritionally acceptablecarriers, and nutraceutically or nutritionally acceptable vehicles.

Suitable pharmaceutically acceptable excipients, carriers and vehiclesinclude processing agents and drug delivery modifiers and enhancers,such as, for example, calcium phosphate, magnesium stearate, talc,monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose,hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes,ion exchange resins, and the like, as well as combinations of any two ormore thereof. Other suitable pharmaceutically acceptable excipients aredescribed in “Remington's Pharmaceutical Sciences,” Mack Pub. Co., NewJersey (1991), and “Remington: The Science and Practice of Pharmacy,”Lippincott Williams & Philadelphia, 20th edition (2003) and 21st edition(2005), incorporated herein by reference.

A pharmaceutical composition can comprise a unit dose formulation, wherethe unit dose is a dose sufficient to have a therapeutic or suppressiveeffect. The unit dose may be sufficient as a single dose to have atherapeutic or suppressive effect. Alternatively, the unit dose may be adose administered periodically in a course of treatment or suppressionof a disorder. A unit dose can contain a therapeutically effectiveamount of a composition disclosed herein. Alternatively, a unit dose cancontain a physiologically effective amount of a composition disclosedherein.

Pharmaceutical compositions containing the compounds of the inventionmay be in any form suitable for the intended method of administration,including, for example, a solution, a suspension, or an emulsion. Liquidcarriers are typically used in preparing solutions, suspensions, andemulsions. Liquid carriers contemplated for use in the practice of thepresent invention include, for example, water, saline, pharmaceuticallyacceptable organic solvent(s), pharmaceutically acceptable oils or fats,and the like, as well as mixtures of two or more thereof. The liquidcarrier may contain other suitable pharmaceutically acceptable additivessuch as solubilizers, emulsifiers, nutrients, buffers, preservatives,suspending agents, thickening agents, viscosity regulators, stabilizers,and the like. Suitable organic solvents include, for example, monohydricalcohols, such as ethanol, and polyhydric alcohols, such as glycols.Suitable oils include, for example, soybean oil, coconut oil, olive oil,safflower oil, cottonseed oil, and the like. For parenteraladministration, the carrier can also be an oily ester such as ethyloleate, isopropyl myristate, and the like. Compositions of the presentinvention may also be in the form of microparticles, microcapsules,liposomal encapsulates, and the like, as well as combinations of any twoor more thereof.

The compositions, as described above, can be prepared as nutritionalformulations such as foods, including medical or functional foods anddietary supplements. A “medical or functional food” is defined as beingconsumed as part of a usual diet but which has been demonstrated to havephysiological benefits and/or to reduce the risk of chronic disease,beyond basic nutritional functions. A “dietary supplement” is defined asa product that is intended to supplement the human diet and is typicallyprovided in the form of a pill, capsule, tablet, or like formulation. Byway of example, but not limitation, a dietary supplement may include oneor more of the following ingredients: vitamins, minerals, herbs,botanicals, amino acids, dietary substances intended to supplement thediet by increasing total dietary intake, and concentrates, metabolites,constituents, extracts or combinations of any of the foregoing. Dietarysupplements may also be incorporated into food stuffs, such asfunctional foods designed to promote health or to prevent disease ordisorders. If administered as a medicinal preparation, the compositioncan be administered, either as a prophylaxis or treatment, to a patientin any of a number of methods. The subject compositions may beadministered alone or in combination with other pharmaceutical agentsand can be combined with a physiologically acceptable carrier thereof.The effective amount and method of administration of the particularformulation can vary based on the individual subject, the stage ofdisease, and other factors evident to one skilled in the art. During thecourse of the treatment, the concentration of the subject compositionsmay be monitored (for example, blood plasma levels may be monitored) toinsure that the desired level is maintained.

The term “nutraceutical” has been used to refer to any substance that isa food or a part of a food and provides medical or health benefits,including the prevention and treatment of disease. Hence, compositionsfalling under the label “nutraceutical” may range from isolatednutrients, dietary supplements and specific diets to geneticallyengineered designer foods, herbal products, and processed foods such ascereals, soups and beverages. In a more technical sense, the term hasbeen used to refer to a product isolated or purified from foods, andgenerally sold in medicinal forms not usually associated with food anddemonstrated to have a physiological benefit or provide protectionagainst chronic disease. Suitable nutraceutically acceptable excipientsmay include liquid solutions such as a solution comprising a vegetable-and/or animal- and/or fish-derived oil.

Time-release or controlled release delivery systems may be used, such asa diffusion controlled matrix system or an erodible system, as describedfor example in: Lee, “Diffusion-Controlled Matrix Systems”, pp. 155-198and Ron and Langer, “Erodible Systems”, pp. 199-224, in “Treatise onControlled Drug Delivery”, A. Kydonieus Ed., Marcel Dekker, Inc., NewYork 1992. The matrix may be, for example, a biodegradable material thatcan degrade spontaneously in situ and in vivo for, example, byhydrolysis or enzymatic cleavage, e.g., by proteases. The deliverysystem may be, for example, a naturally occurring or synthetic polymeror copolymer, for example in the form of a hydrogel. Exemplary polymerswith cleavable linkages include polyesters, polyorthoesters,polyanhydrides, polysaccharides, poly(phosphoesters), polyamides,polyurethanes, poly(imidocarbonates) and poly(phosphazenes).

The compounds of the invention may be administered enterally, orally,parenterally, buccally, sublingually, by inhalation (e.g. as mists orsprays), rectally, vaginally, or topically in dosage unit formulationscontaining conventional nontoxic pharmaceutically acceptable carriers,adjuvants, and vehicles as desired. For example, suitable modes ofadministration include oral, subcutaneous, transdermal, transmucosal,iontophoretic, intravenous, intraarterial, intramuscular, intraocular,intraperitoneal, intranasal (e.g. via nasal mucosa), rectal,gastrointestinal, and the like, and directly to a specific or affectedorgan or tissue. For delivery to the central nervous system, spinal andepidural administration, or administration to cerebral ventricles, canbe used. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. The compounds are mixed with pharmaceutically acceptablecarriers, adjuvants, and vehicles appropriate for the desired route ofadministration. Oral administration is a preferred route ofadministration, and formulations suitable for oral administration arepreferred formulations. The compounds described for use herein can beadministered in solid form, in liquid form, in aerosol form, or in theform of tablets, pills, powder mixtures, capsules, granules,injectables, creams, solutions, suppositories, enemas, colonicirrigations, emulsions, dispersions, food premixes, and in othersuitable forms. The compounds can also be administered in liposomeformulations. The compounds can also be administered as prodrugs, wherethe prodrug undergoes transformation in the treated subject to a formwhich is therapeutically effective. Additional methods of administrationare known in the art.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in propylene glycol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution, in addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordi-glycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also compriseadditional substances other than inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33 et seq (1976).

In a preferred embodiment, the compositions are provided to the patientas either a food or a food supplement. For example, when provided as afood the compositions of the present invention are combined withmaterial primarily made up of protein, carbohydrate and/or fat that isused in the body, preferably a human body, to sustain growth, repair,and vital processes, and to furnish energy. When provided as a foodsupplement, the compositions comprise selected substances such that theycan be eaten at or about the same time as a food. The food supplementsare generally eaten within about one hour before or after the food iseaten, typically within about one-half hour before or after the food iseaten, preferably within about 15 minutes of when the food is eaten, andfurther preferably within one to five minutes of the time the food iseaten. The food supplement can also be eaten at the same time as thefood, or even with the food.

The invention also provides articles of manufacture and kits containingmaterials useful for treating or suppressing PDD including Autism or forreducing the symptoms of one or more symptoms of PDD. The invention alsoprovides kits comprising any one or more of the compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula Ia,Formula IIa, Formula IIIc, Formula IVa, Formula Va, Formula VIa, FormulaIb, Formula Ib-R, Formula Ib-S, Formula Ic, Formula Ic-RRR, FormulaIc-SRR, Formula Ic-RSR, Formula Ic-RRS, Formula Ic-SSR, Formula Ic-SRS,Formula Ic-RSS, Formula Ic-SSS, Formula IIIb, Formula IIIc, FormulaIIIc-RRR, Formula IIIc-SRR, Formula IIIc-RSR, Formula IIIc-RRS, FormulaIIIc-SSR, Formula IIIc-SRS, Formula IIIc-RSS, Formula IIIc-SSS, FormulaId, Formula IId, Formula IIId, or Formula IVd, or mixtures thereof. Insome embodiments, the kit of the invention comprises the containerdescribed above.

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with a pervasivedevelopmental disorder, including an autistic spectrum disorder, or tosuppress a pervasive developmental disorder, such as an autisticspectrum disorder in an individual.

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with an attentiondeficit disorder, including attention deficit/hyperactivity disorder(ADHD), or to suppress an attention deficit disorder, such as attentiondeficit/hyperactivity disorder (ADHD) in an individual.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost to which the active ingredient is administered and the particularmode of administration. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, body area, body mass index (BMI),general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the type,progression, and severity of the particular disease undergoing therapy.The pharmaceutical unit dosage chosen is usually fabricated andadministered to provide a defined final concentration of drug in theblood, tissues, organs, or other targeted region of the body. Thetherapeutically effective amount or physiologically effective amount fora given situation can be readily determined by routine experimentationand is within the skill and judgment of the ordinary clinician.

Examples of dosages which can be used are an effective amount within thedosage range of about 0.1 mg/kg to about 300 mg/kg body weight, orwithin about 1.0 mg/kg to about 100 mg/kg body weight, or within about1.0 mg/kg to about 50 mg/kg body weight, or within about 1.0 mg/kg toabout 30 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kgbody weight, or within about 10 mg/kg to about 100 mg/kg body weight, orwithin about 50 mg/kg to about 150 mg/kg body weight, or within about100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg toabout 250 mg/kg body weight, or within about 200 mg/kg to about 300mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg bodyweight. Compounds of the present invention may be administered in asingle daily dose, or the total daily dosage may be administered individed dosage of two, three or four times daily.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents used in the treatment or suppression ofdisorders. If compounds are administered together, they need not beadministered by the same route, or in the same formulation. However,they can be combined into one formulation as desired.

Representative agents useful in combination with the compounds of theinvention for the treatment or suppression of PDD, ASD, or ADHD symptomsinclude, but are not limited to, Coenzyme Q10 and antioxidant compoundsand/or drugs, such as but not limited to carnitine, quercetine,mangosteen, acai, uridine, N-acetyl cysteine (NAC), vitamin A, vitaminC, lutein, beta-carotene, lycopene, and glutathione. Other agents usefulin combination with the compounds of the invention are compounds and/ordrugs that have an effect on the neurotransmitters, particularlyserotonin and dopamine, that include antidepressants, anti-anxietydrugs, antispasmodics, neuroleptics and atypical neuroleptics, andstimulants. Antidepressants include but are not limited to SelectiveSerotonin Reuptake Inhibitors (SSRIs) (fluoxetine (Prozac); fluvoxamine(Luvox); paroxetine (Paxil); sertraline (Zoloft); citalopram (Celexa));Tricyclic antidepressants (amitriptyline (Elavil);amitriptyline/chlordiazepoxide (Limbitrol); amoxapine (Asendin);clomipramine (Anafranil); desipramine (Norpramin); doxepin (Sinequan);imipramine (Tofranil); nortriptyline (Avenytl, Pamelor); protriptyline(Vivactil); trimipramine (Surmontil)); MAO Inhibitors (moclobemide(Aurorex); phenelzine (Nardil); tranylcypromine sulfate (Parnate));Buproprion; Lithium; Mirtazapine; Nefazodone (Serzone); Reboxetine(Edronax); Venlafaxine (Effexor, Effexor XR); and “natural”anti-depressants such as St. John's Wart. Anti-anxiety drugs include butare not limited to alprazolam (Xanax); chlordiazepoxide (Librium);clonazepam (Klonopin); clorazepate (Tranxene); diazepam (Valium);lorazepam (Ativan); oxazepam (Serax); and prazepam (Centrax).Antispasmodic medications include but are not limited to carmazepine(Tegretol); clonazepam (Klonopin); ethosuximide (Zarontin); ethotoin(Peganone); fosphenytoin (Cerebyx); gabapentin (Neurontin); lamotrigine(Lamictal); mephenytoin (Mesantoin); phenobarbital (Luminol, Solfoton);phenytoin (Dilantin); primidone (Mysoline); toiramate (Topamax);valproic acid (Depakene); divalproex sodium (Depakote, DepakoteSprinkles); and Gabapentin (Neurontin). Stimulants include but are notlimited to dextroamphetamine sulfate (Das, Dexampex, Dexedrine,Dexedrine Spansules, Dextrostat, Ferndex, Oxydess);dextroamphetamine/amphetamine (Adderall); methamphetamine (MTH);methylphenidate hydrochloride (Ritalin); and pemoline (Cyclert); andphenylpropanolamine (PPA). Atypical neuroleptics include but are notlimited to clozapine (Clozaril); olanzapine (Zyprexa); risperidone(Risperdal); quetiapine (Seroquel); and ziprasidone (Zeldox).

The compounds of the invention can be administered in combination withone or more minerals, such as, but not limited to, iron, calcium,potassium, zinc, manganese, phosphorous, chromium, magnesium, manganese,molybdenum, tin, nickel sulfur, selenium, copper, cobalt, chloride,fluoride, and iodine. The minerals may be administered in large or traceamounts. The compounds can be administered together with the minerals inone formulation, or in different formulations.

When additional active agents are used in combination with the compoundsof the present invention, the additional active agents may generally beemployed in therapeutic amounts as indicated in the Physicians' DeskReference (PDR) 53rd Edition (1999), or such therapeutically usefulamounts as would be known to one of ordinary skill in the art.

The compounds of the invention and the other therapeutically activeagents can be administered at the recommended maximum clinical dosage orat lower doses. Dosage levels of the active compounds in thecompositions of the invention may be varied so as to obtain a desiredtherapeutic response depending on the route of administration, severityof the disease and the response of the patient. When administered incombination with other therapeutic agents, the therapeutic agents can beformulated as separate compositions that are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

The invention will be further understood by the following non-limitingexample.

EXAMPLE Screening Compounds of the Invention in Human Dermal Fibroblastsfrom Autistic Patients

A screen was performed to identify compounds effective for theamelioration of ASD. Test samples, and solvent controls were tested fortheir ability to rescue ASD fibroblasts stressed by addition ofL-buthionine-(S,R)-sulfoximine (BSO).

MEM (a medium enriched in amino acids and vitamins, catalog no. Gibco11965) and Fetal Calf Serum were obtained from Invitrogen. Basicfibroblast growth factor and epidermal growth factor were purchased fromPeproTech. Penicillin-streptomycin-glutamine mix, L-buthionine(S,R)-sulfoximine, and insulin from bovine pancreas were purchased fromSigma. Calcein AM was purchased from Molecular Probes. Cell culturemedium (ATP) was made by combining 75 ml Fetal Calf Serum, 100 U/mlpenicillin, 100 μg/ml streptomycin, 2 mM glutamine, 10 ng/ml EGF, and 10ng/ml bFGF; MEM EBS was added to make the volume up to 500 ml. A 10 mMBSO solution was prepared by dissolving 444 mg BSO in 200 ml of mediumwith subsequent filter-sterilization. During the course of theexperiments, this solution was stored at +4° C. The cells were obtainedfrom Dr. J. M. Shoffner Medical Neurogenetics, Atlanta, Ga. and weregrown in 10 cm tissue culture plates. Every week, they were split at a1:3 ratio.

The samples were supplied in 1.5 ml glass vials. The compounds werediluted with DMSO, ethanol or PBS to result in a 5 mM stock solution.Once dissolved, they were stored at −20° C.

The samples were screened according to the following protocol:

A culture with ASD fibroblasts was started from a 1 ml vial withapproximately 500,000 cells stored in liquid nitrogen. Cells werepropagated in 10 cm cell culture dishes by splitting every week in aratio of 1:3 until nine plates were available. Once confluent,fibroblasts were harvested. For 54 micro titer plates (96 well-MTP) atotal of 14.3 million cells (passage eight) were re-suspended in 480 mlmedium, corresponding to 100 medium with 3,000 cells/well. The remainingcells were distributed in 10 cm cell culture plates (500,000cells/plate) for propagation. The plates were incubated overnight at 37°C. in an atmosphere with 95% humidity and 5% CO₂ to allow attachment ofthe cells to the culture plate.

MTP medium (243 μl) was added to a well of the microtiter plate. Thetest compounds were unfrozen, and 7.5 μl of a 5 mM stock solution wasdissolved in the well containing 243 μl medium, resulting in a 150 μMmaster solution. Serial dilutions from the master solution were made.The period between the single dilution steps was kept as short aspossible (generally less than 1 second).

Plates were kept overnight in the cell culture incubator. The next day,10 μl of a 10 mM BSO solution were added to the wells, resulting in a 1mM final BSO concentration. Forty-eight hours later, three plates wereexamined under a phase-contrast microscope to verify that the cells inthe 0% control (wells E1-H1) were clearly dead. The medium from allplates was discarded, and the remaining liquid was removed by gentlytapping the plate inversed onto a paper towel.

100 μl of PBS containing 1.2 μM Calcein AM were then added to each well.The plates were incubated for 50-70 minutes at room temperature. Afterthat time the PBS was discarded, the plate gently tapped on a papertowel and fluorescence (excitation emission wavelengths of 485 nm and525 nm, respectively) was read on a Gemini fluorescence reader. Data wasimported into Microsoft Excel (EXCEL is a registered trademark ofMicrosoft Corporation for a spreadsheet program) and used to calculatethe EC₅₀ concentration for each compound.

The compounds were tested three times, i.e., the experiment wasperformed three times, the passage number of the cells increasing by onewith every repetition.

The solvents (DMSO, ethanol, PBS) neither had a detrimental effect onthe viability of non-BSO treated cells nor did they have a beneficialinfluence on BSO-treated fibroblasts even at the highest concentrationtested (1%). None of the compounds showed auto-fluorescence. Theviability of non-BSO treated fibroblasts was set as 100%, and theviability of the BSO- and compound-treated cells was calculated asrelative to this value.

Certain compounds of the present invention such as:2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione and2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dioneand 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione exhibitedprotection against ASD with an EC₅₀ of less than about 150 nM.

In general, the nomenclature used in this Application was generated withthe help of naming package within the ChemOffice® version 11.0 suite ofprograms by CambridgeSoft Corp (Cambridge, Mass.).

What is claimed is:
 1. A compound selected from the group consisting of:

and solvates and hydrates thereof.
 2. The compound of claim 1 selectedfrom the group consisting of:

and solvates and hydrates thereof.
 3. The compound of claim 1 of theformula:


4. The compound of claim 1 selected from the group consisting of:

and solvates and hydrates thereof.
 5. The compound of claim 1 of theformula:


6. A composition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 7. A composition comprising the compound of claim 2and a pharmaceutically acceptable carrier.
 8. A composition comprisingthe compound of claim 3 and a pharmaceutically acceptable carrier.
 9. Acomposition comprising the compound of claim 4 and a pharmaceuticallyacceptable carrier.
 10. A composition comprising a compound of claim 5and a pharmaceutically acceptable carrier.
 11. A food, medical food,functional food, food supplement, or dietary supplement comprising acompound of claim 1 and a physiologically or nutritionally acceptablecarrier, adjuvant, excipient, buffer, or diluent.